Adenylate kinase (ATP/GTP:AMP phosphotransferase) plays a key role in the regulation of cellular levels of ATP. ATP is a key precursor in DNA and RNA synthesis in growing cells and provides the primary source of biochemical energy in cells. Adenylate kinase (AK) is found in almost all cell types and is especially abundant in cells having high rates of ATP synthesis and utilization such as the liver, heart, and skeletal muscles. Recent studies have demonstrated a major function for AdK in transferring high energy phosphoryls from metabolic processes generating ATP to cellular components consuming ATP (Zeleznikar, R J et al (1995) J. Biol. Chem. 270(13): 7311-7319). Thus AdK may have a pivitol role in maintaining energy production in cells, particularly those having a high rate of growth or metabolism. Inhibition of various steps in the synthesis of ATP has been the basis of many antiproliferative drugs for treatment of cancer and viral infections. AK deficiency has also been linked to hemolytic anemia and neurological disorders such as neurofibromatosis (Xu, G. et al. (1992) Genomics 13:537-42).
Three isozymes of AK have been identified in vertebrates, AK1, AK2, and AK3 (Yamada, M. et al. (1989) J. Biol. Chem. 264: 19192-99; Xu et al., supra). AK1 is a cytosolic enzyme present in skeletal muscle, brain, and erythrocytes, and AK2 is associated with the mitochondrial membrane in liver, kidney, spleen, and heart. Both AK1 and AK2 use ATP as the phosphate donor substrate. AK3 is also a mitochondrial enzyme, primarily found in liver and heart, but uses GTP as the phosphate donor. AK2 and AK3 are unusual in that they do not have a cleavable N-terminal sequence directing them to the mitochondrial membrane as do most mitochondrial proteins (Yamada et al., supra). Targeting of these proteins to the mitochondria appears to be governed by a non-cleavable N-terminal sequence that contains a positively charged amphipathic region. This targeting sequence also contains a consensus sequence, GXXGXGK, which is commen to all nucleotide kinases and functions in binding the mononucleotide substrate to the enzyme and in enzyme catalysis. The C-terminal 30-35 amino acids of AK3 also appear to be involved in the enzyme activity.
The discovery of polynucleotides encoding a novel mitochondrial adenylate kinase and the molecules themselves satisfies a need in the art by providing new diagnostic or therapeutic compositions useful in treating or preventing cancer, neurological disorders, and immunological disorders.